title: Calcineurin interacts with the serotonin transporter C-terminus to modulate its plasma membrane expression and serotonin uptake.
abstract: Homeostasis of serotonergic transmission critically depends on the rate of serotonin reuptake via its plasma membrane transporter (SERT). SERT activity is tightly regulated by multiple mechanisms, including physical association with intracellular proteins and post-translational modifications, such as phosphorylation, but these mechanisms remain partially understood. Here, we show that SERT C-terminal domain recruits both the catalytic and regulatory subunits of the Ca(2+)-activated protein phosphatase calcineurin (CaN) and that the physical association of SERT with CaN is promoted by CaN activity. Coexpression of constitutively active CaN with SERT increases SERT cell surface expression and 5-HT uptake in HEK-293 cells. It also prevents the reduction of 5-HT uptake induced by an acute treatment of cells with the protein kinase C activator β-PMA and concomitantly decreases PMA-elicited SERT phosphorylation. In addition, constitutive activation of CaN in vivo favors 5-HT uptake in the adult mouse brain, whereas CaN inhibition reduces cerebral 5-HT uptake. Constitutive activation of CaN also decreases immobility in the forced swim test, indicative of an antidepressant-like effect of CaN. These results identify CaN as an important regulator of SERT activity in the adult brain and provide a novel molecular substrate of clinical interest for the understanding of increased risk of mood disorders in transplanted patients treated with immunosuppressive CaN inhibitors.
authors.affiliation: Centre National de la Recherche Scientifique, UMR-5203, Institut de Génomique Fonctionnelle, F-34094 Montpellier, France, Institut National de la Santé et de la Recherche Médicale, U661, F-34094 Montpellier, France, Université Montpellier 1, F-34094 Montpellier, France, Université Montpellier 2, F-34094 Montpellier, France, and Brain Research Institute, Medical Faculty of the University of Zürich and Department of Health Science and Technology of the Swiss Federal Institute of Technology, CH-8057 Zürich, Switzerland.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Seimandi
authors.forename: Pascal
authors.initials: P
authors.lastname: Seyer
authors.forename: C Sehwan
authors.initials: CS
authors.lastname: Park
authors.forename: Franck
authors.initials: F
authors.lastname: Vandermoere
authors.forename: Benjamin
authors.initials: B
authors.lastname: Chanrion
authors.forename: Joël
authors.initials: J
authors.lastname: Bockaert
authors.forename: Isabelle M
authors.initials: IM
authors.lastname: Mansuy
authors.forename: Philippe
authors.initials: P
authors.lastname: Marin
mesh_terms: D000818:Animals; D015153:Blotting, Western; D019703:Calcineurin / Q000737:chemistry / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D047468:Immunoprecipitation; D013058:Mass Spectrometry; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism*; D011485:Protein Binding; D012701:Serotonin / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000737:chemistry / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology*
chemical_list: D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; D012701:Serotonin; D019703:Calcineurin